Delineating a parietal-anterior cingulate-claustrum circuit underlying cognitive control and attention
Treatments are urgently needed for cognitive dysfunction in psychiatric patients. Given the link between such
dysfunction and outcome in patients, large numbers of clinical trials were conducted with companies attempting
to be ‘first-to-market’. In the rush however, preclinical studies used had limited validity to the cognitive domains
reportedly targeted. Thus, circuit-engagement of the cognitive domain tested was rarely if-at-all verified and all
clinical trials to-date have failed. New paradigms have emerged with reported relevance to domains affected in
psychiatry, but little opportunity to validate circuits underlying these behaviors, let-alone drugs that modulate
such circuits and behavior, have arisen. This application will utilize a circuit-targeted approach to confirm the
utility of the 5-choice continuous performance test (5C-CPT) to measure cognitive control and attention across
multiple psychiatric disorders. Specific Aim 1 will optimize the touchscreen 5C-CPT for parametric
manipulation. The 5C-CPT exists for mice, rats, and humans, with EEG & fMRI versions. The task has always
been standard however, primarily in 5-hole operant chambers, but a touchscreen version with parametric
manipulations within the task would improve translatability to human testing and enable task performance-based
consistency. Backward masking of stimuli have been used in cognitive control tasks previously, but only recently
used in human 5C-CPT studies. Here, we will demonstrate that such masked trials enable parametric
assessment of 5C-CPT performance in mice. Specific Aim 2 will determine the pharmacological sensitivity
of the touchscreen 5C-CPT. After developing the task, it is important to confirm that it is sensitive to
manipulations, including those available for use in humans for pharmacological predictive validation. We
demonstrated that modafinil improves healthy human participant performance of the standard 5C-CPT, while
scopolamine impairs mouse performance. Here, we will confirm that modafinil and scopolamine similarly affect
this masked touchscreen 5C-CPT, while predicting that a dopamine D4 receptor agonist would improve cognitive
control. We will confirm that modafinil rescues scopolamine-induced deficits, avoiding receptor tautological
complications. Specific Aim 3 will confirm the role of the anterior cingulate cortex (ACC)¿claustrum and
claustrum¿parietal cortex (PC) circuit underlying this masked touchscreen 5C-CPT performance.
Consistent with human CPTs, we confirmed the necessity of the PC for mouse 5-choice (5C-)CPT performance.
We hypothesize that a ACC to claustrum projection is important during more cognitively demanding trials (from
parametric manipulations), while a claustrum to PC projection occurs is important for selecting whether to
respond or not during trials. Using fiber photometry and optogenetic techniques, we will confirm both the
activation and necessity of this circuit respectively, including changes in activity as a direct result of
pharmacological manipulation. Thus, circuitry underlying cognitive control will be identified, as will
pharmacological treatments affecting this circuit that are readily testable in healthy human participants.
